The aim of the project is to develop viral agents which can replicate and lyse tumor cells but not cells of normal differentiated tissue. Herpes simplex virus (HSV) has the natural ability to infect and destroy cells in which they multiply. Genetic mutations which render the virus non-pathogenic but permissive for viral replication are considered. We will perform two main tasks in Phase I. First we will develop non-pathogenic HSV viral agents that have enhanced capabilities to kill tumor cells. Genetic mutations as well as foreign genes which enhance the therapeutic effect of the viral agents will be used. Second, the oncolytic potential of the viral agents will be analyzed on tumor cell lines derived from human cancer. This will allow us to test the feasibility of this approach in animal model system in Phase II studies. In Phase II, we will extend the analysis to animals in which the capacity of the viral agents to destroy human tumors grown in scid mice or primates will be assessed. This work will be pursued in collaboration with research laboratories or commercial companies to bring this protocol into Phase III clinical trials. PROPOSED COMMERCIAL APPLICATION: We will develop novel therapeutics based on the herpes simplex virus (HSV) system in the treatment of human cancer. In Phase I we will construct and develop novel HSV agents which are nonpathogenic but have the enhanced capacities to lyse tumor cell mass in the treatment of human cancer and test the feasibility of these viral agents to destroy tumor cells. In Phase II we will develop the system in animal models for subsequent Phase III human testing and commercialization.